Active Estrogen Receptor-alpha Signaling in Ovarian Cancer Models and Clinical Specimens

Purpose: High-grade serous ovarian cancer (HGSOC) is an aggressive disease with few available targeted therapies. Despite high expression of estrogen receptor-alpha (ER alpha) in approximately 80% of HGSOC and some small but promising clinical trials of endocrine therapy, ER alpha has been understudied as a target in this disease. We sought to identify hormone-responsive, ER alpha-dependent HGSOC. Experimental Design: We characterized endocrine response in HGSOC cells across culture conditions [two-dimensional (2D), three-dimensional (3D), forced suspension] and in patient-derived xenograft (PDX) explants, assessing proliferation and gene expression. Estrogen-regulated transcriptome data were overlapped with public datasets to develop a comprehensive panel of ER alpha target genes. Expression of this panel and ER alpha H-score were assessed in HGSOC samples from patients who received endocrine therapy. Time on endocrine therapy was used as a surrogate for clinical response. Results: Proliferation is ER alpha-regulated in HGSOC cells in vitro and in vivo, and is partly dependent on 3D context. Transcriptomic studies identified genes shared by cell lines and PDX explants as ER alpha targets. The selective ER alpha downregulator (SERD) fulvestrant is more effective than tamoxifen in blocking ER alpha action. ER alpha H-score is predictive of efficacy of endocrine therapy, and this prediction is further improved by inclusion of target gene expression, particularly IGFBP3. Conclusions: Laboratory models corroborate intertumor heterogeneity of endocrine response in HGSOC but identify features associated with functional ER alpha and endocrine responsiveness. Assessing ER alpha function (e.g., IGFBP3 expression) in conjunction with H-score may help select patients who would benefit from endocrine therapy. Preclinical data suggest that SERDs might be more effective than tamoxifen. (C) 2017 AACR.